Methods of treating prader willi syndrome and conditions associated with low basal metabolic rate or hyperphagia using a katp channel opener

ABSTRACT

This invention relates to treating Prader-Willi Syndrome (PWS) using a KATP channel opener. The channel opener may be coadministered with other therapies used to treat PWS, such as human growth hormone, a wakefulness promoting agent, or a psychiatric or mood stabilizing drug, thereby allowing the baseline dosages of these other therapies to be decreased or making these other therapies unnecessary. The invention also relates to treating PWS based on the PWS nutritional phase of a patient, to prevent the patient&#39;s PWS nutritional phase from progressing or shift the patient&#39;s PWS nutritional phase back to an earlier phase. The invention further relates to treating PWS, and conditions associated with low basal metabolic rate or hyperphagia, with the KATP channel opener based on a patient&#39;s blood ketone levels.

FIELD OF THE INVENTION

This invention relates to treating Prader-Willi Syndrome (PWS) andconditions affecting basal metabolic rate using a K_(ATP) channelopener. The K_(ATP) channel opener may be coadministered with othertherapies used to treat PWS, such as human growth hormone, a wakefulnesspromoting agent, or a psychiatric/mood stabilizing medication, which mayallow the dose of these other therapies to be reduced relative to thedose that would otherwise be given to a patient with PWS in the absenceof the K_(ATP) channel opener (e.g., baseline dose). The K_(ATP) channelopener may also obviate the need for the use of the other therapies usedto treat PWS, such that PWS may be treated without human growth hormone,a wakefulness promoting agent, or a psychiatric/mood stabilizingmedication. The K_(ATP) channel opener dosage may also be administeredaccording to the PWS nutritional phase of a patient. The K_(ATP) channelopener may also be administered to prevent the PWS patient's PWSnutritional phase from progressing, or to shift the PWS nutritionalphase back to an earlier phase. The K_(ATP) channel opener dosage fortreating PWS or conditions associated with low basal metabolic rate orhyperphagia, such as obesity, may be modulated according to a patient'sblood ketone level or diet.

BACKGROUND OF THE INVENTION

Prader-Willi syndrome (PWS) is a complex neurobehavioral disorder whichis due to the absence of normally active paternally expressed genes fromthe chromosome 15q11-q13 region. PWS is an imprinted condition with70-75% of the cases due to a de novo deletion in the paternallyinherited chromosome 15 11-q13 region, 20-30% from maternal uniparentaldisomy 15 (UPD), and the remaining 2-5% from either microdeletions orepimutations of the imprinting center (i.e., imprinting defects).Clinical features of PWS include hypotonia and poor feeding in infancywhich almost always requires some type of assisted feeding for a periodof time, followed by hyperphagia as the child ages. Obesity typicallybegins around 2 years of age if the diet is not restricted. Behavioralproblems and neuroendocrine abnormalities are also characteristic ofPWS.

Given the complexity of PWS, its symptoms are treated with a number ofdifferent medications, including human growth hormone (GH),psychiatric/mood stabilizing medications, and wakefulness promotingagents. Many of the aforementioned drugs that are currently used totreat PWS have undesirable side effects. Accordingly, there is a need inthe art to reduce these side effects by providing a way to reduce thedosages of the drugs used to treat PWS, or eliminate the need to usesuch drugs.

SUMMARY OF THE INVENTION

Provided herein is a method for treating Prader-Willi Syndrome, whichmay comprise administering a K_(ATP) channel opener and a human growthhormone (GH) to a patient in need thereof. The dose of human growthhormone may be reduced in comparison to a baseline or adjusted GH dose.The baseline or adjusted GH dose may be reduced by at least 10, 20, 50,80, 90, or 100%.

Further provided herein is a method for treating Prader-Willi Syndrome,which may comprise administering a K_(ATP) channel opener and apsychiatric or mood stabilizing drug to a patient in need thereof. Thedose of the psychiatric or mood stabilizing drug may be reduced incomparison to a baseline psychiatric or stabilizing drug dose. Thebaseline psychiatric medication dose may be reduced by at least 10, 20,50, 80, 90, or 100%. The psychiatric or mood stabilizing drug may be aselective serotonin reuptake inhibitor (SSRI), a norepinephrine reuptakeinhibitor (NRI), a noradrenergic and specific serotonergicantidepressant (NaSSA), a serotonin-norepinephrine reuptake inhibitor(SNRI), a serotonin antagonist and reuptake inhibitor (SARI), anorepinephrine-dopamine reuptake inhibitor, a selective serotoninreuptake enhancer, a norepinephrine-dopamine disinhibitor, a tricyclicantidepressant, a tetracyclic antidepressant, a monoamine oxidaseinhibitor (MAOI), N-acetylcysteine, cysteamine, oxytocin, a moodstabilizer, an anticonvulsant, a metabotropic glutamate receptormodulator, a typical antipsychotic, or an atypical antipsychotic.

Also provided herein is a method for treating Prader-Willi Syndrome,which may comprise administering a K_(ATP) channel opener and awakefulness promoting agent to a patient in need thereof. The dose ofthe wakefulness promoting agent may be reduced in comparison to abaseline wakefulness promoting agent dose. The baseline wakefulnesspromoting agent dose may be reduced by at least 10, 20, 50, 80, 90, or100%. The wakefulness promoting agent may be a stimulant, anamphetamine, a norepinephrine reuptake inhibitor (NRI), anorepinephrine-dopamine reuptake inhibitor (NDRI), a tricyclicantidepressant, a serotonin-norepinephrine reuptake inhibitor (SNRI), anH3-receptor antagonist, an orexin agonist, sodium oxybate, caffeine, ora eugeroic.

Further provided herein is a method for treating Prader-Willi Syndromewhich may comprise administering a K_(ATP) channel opener to a patientin need thereof. The patient may be in PWS nutritional phase 0, 1a, 1b,2a, 2b, 3, or 4. The patient's PWS nutritional phase may be preventedfrom progressing to a later phase. The patient may be in PWS nutritionalphase 1a, 1b, 2a, or 2b, and the patient's PWS nutritional phase may beprevented from progressing to phase 1b, 2a, 2b, or 3. The patient's PWSnutritional phase may be shifted back to an earlier PWS nutritionalphase. The patient may be in PWS nutritional phase 3 or 4, and thepatient's PWS nutritional phase may be shifted back to phase 1a, 1b, 2a,or 2b.

Also provided herein is a method for treating a disease or conditionselected from Prader-Willi Syndrome, a condition associated with lowbasal metabolic rate, and a condition associated with hyperphagia. Themethod may comprise administering a K_(ATP) channel opener to a patientin need thereof, and the patient's blood ketone level may be less than atarget level selected from 3.0, 2.5, 2.0, 1.5, 1.0, 0.6, 0.5, 0.4, 0.3,0.2, and 0.1 mmol/mL. The method may further comprise the step ofadministering a subsequent dose of the K_(ATP) channel opener to thepatient. The subsequent dose may be higher than the previous dose if thepatient's blood ketone level is less than or equal to the target levelafter administration of the previous dose, and the subsequent dose maybe equal to or less than the previous dose if the patient's blood ketonelevel is greater than or equal to the target level after administrationof the previous dose.

Also provided herein is a method for treating autistic symptoms orbehaviors associated with Prader-Willi Syndrome, which may compriseadministering a K_(ATP) channel opener to a patient in need thereof.

DETAILED DESCRIPTION

The inventor has made the surprising discovery that administering aK_(ATP) channel opener (e.g., diazoxide) in combination with othertherapies used to treat Prader-Willi Syndrome (PWS) allows the dosagesof these other therapies to be reduced relative to the dosages thatwould ordinarily be administered in the absence of the K_(ATP) channelopener, or to be entirely eliminated from a PWS treatment regimen. Forexample, various symptoms of PWS can be treated with human growthhormone, wakefulness promoting agents (e.g., modafinil), andpsychiatric/mood stabilizing medications. The standard doses of suchtherapies are associated with undesirable side effects, such as insulinresistance in the case of growth hormone. Coadministering a K_(ATP)channel opener allows lower doses of these other PWS therapies to beused, thereby resulting in fewer or reduced side effects. The inventorhas also unexpectedly found that the efficacy of a K_(ATP) channelopener is affected by the nutritional phase of a patient's PWS.Therefore, the K_(ATP) channel opener may be administered according tothe PWS nutritional phase of the patient, and may prevent the patient'sPWS nutritional phase from progressing or shift the patient's PWSnutritional phase back to an earlier phase. Surprisingly, the inventorhas also discovered that PWS and conditions associated with low basalmetabolic rate or hyperphagia can be treated by modulating the dose ofK_(ATP) channel opener based on a patient's blood ketone level and/ordiet.

1. DEFINITIONS

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting. As used in thespecification and the appended claims, the singular forms “a,” “an” and“the” include plural referents unless the context clearly dictatesotherwise.

For recitation of numeric ranges herein, each intervening number therebetween with the same degree of precision is explicitly contemplated.For example, for the range of 6-9, the numbers 7 and 8 are contemplatedin addition to 6 and 9, and for the range 6.0-7.0, the numbers 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitlycontemplated.

“Halo” and “halogen” refer to all halogens, that is, chloro (Cl), fluoro(F), bromo (Br), or iodo (I).

“Hydroxyl” and “hydroxy” means the group —OH.

“Substituted oxy” means the group —OR^(aa), where R^(aa) can be alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, or substitutedheterocyclyl.

“Substituted thiol” means the group —SR^(bb), where R^(bb) can be alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, or substitutedheterocyclyl.

“Alkyl” means an alkane-derived radical containing from 1 to 10,preferably 1 to 6, more preferably 1-4, yet more preferably 1-2, carbonatoms. Alkyl includes straight chain alkyl, branched alkyl andcycloalkyl, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,and the like. The alkyl group can be attached at any available point toproduce a stable compound. An “alkylene” is a divalent alkyl.

A “substituted alkyl” means an alkyl group independently substitutedwith 1 or more, e.g., 1, 2, or 3, groups or substituents such as halo,hydroxy, optionally substituted alkoxy, optionally substitutedalkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted amino,optionally substituted amido, amidino, urea optionally substituted withalkyl, amino sulfonyl optionally N-mono- or N,N-di-substituted withalkyl, alkylsulfonylamino, carboxyl, heterocycle, substitutedheterocycle, nitro, cyano, thiol, sulfonylamino or the like attached atany available point to produce a stable compound. In particular, “fluorosubstituted” refers to substitution by 1 or more, e.g., 1, 2, or 3fluorine atoms. “Optionally fluoro substituted” means that substitution,if present, is fluoro. The term “optionally substituted” as used hereinmeans that substitution may, but need not, be present.

“Lower alkyl” means an alkyl group having 1-6 carbon atoms.

A “substituted lower alkyl” means a lower alkyl which is substitutedwith 1 or more, e.g., 1, 2, or 3, groups or substituents, as definedabove, attached at any available point to produce a stable compound.

“Cycloalkyl” means saturated or unsaturated, non-aromatic monocyclic,bicyclic or tricyclic carbon ring systems of 3-8, more preferably 3-6,ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl,adamantyl, and the like. “Cycloalkylene” is a divalent cyclo alkyl.

“Substituted cycloalkyl” means saturated or unsaturated, non-aromaticmonocyclic, bicyclic or tricyclic carbon ring systems of 3-8, morepreferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl,cyclohexyl, adamantyl, and the like independently substituted with 1 ormore, e.g., 1, 2, or 3, groups or substituents such as halo, hydroxy,optionally substituted alkoxy, optionally substituted alkylthio,alkylsulfinyl, alkylsulfonyl, optionally substituted amino, optionallysubstituted amido, amidino, urea optionally substituted with alkyl,aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl,alkylsulfonylamino, carboxyl, heterocycle, substituted heterocycle,nitro, cyano, thiol, sulfonylamino or the like attached at any availablepoint to produce a stable compound.

“Aryl” alone or in combination means phenyl or naphthyl optionallycarbocyclic fused with a cycloalkyl of preferably 5-7, more preferably5-6, ring members.

“Substituted aryl” means an aryl group as defined above independentlysubstituted with 1 or more, e.g., 1, 2, or 3, groups or substituentssuch as halo, hydroxy, optionally substituted alkoxy, optionallysubstituted alkylthio, alkylsulfinyl, alkylsulfonyl, optionallysubstituted amino, optionally substituted amido, amidino, ureaoptionally substituted with alkyl, aminosulfonyl optionally N-mono- orN,N-di-substituted with alkyl, alkylsulfonylamino, carboxyl,heterocycle, substituted heterocycle, nitro, cyano, thiol, sulfonylaminoor the like attached at any available point to produce a stablecompound.

“Alkoxy” means the group —OR^(cc), where R^(cc) is alkyl. “Lower alkoxy”denotes the group —OR^(ccc), where R^(ccc) is lower alkyl

“Substituted alkoxy” means the group —OR^(dd), where R^(dd) issubstituted alkyl. “Substituted lower alkoxy” means the group —OR^(ddd)where R^(ddd) is substituted lower alkyl.

“Alkylthio” or “thioalkoxy” means the group —S—R^(ee), where R^(ee) isalkyl.

“Substituted alkylthio” or “substituted thioalkoxy” means the group—S—R, where R is substituted alkyl.

“Sulfinyl” means the group —S(O)—.

“Sulfonyl” means the group —S(O)₂—.

“Substituted sulfinyl” means the group —S(O)—R^(ff), where R^(ff) isalkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,cycloalkylalkyl, substituted cycloalkylalkyl, heterocyclyl, substitutedheterocyclyl, heterocyclylalkyl, substituted hetereocyclylalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl,substituted heteroaralkyl, aralkyl or substituted aralkyl.

“Substituted sulfonyl” means the group —S(O)₂R^(gg), where R^(gg) isalkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,cycloalkylalkyl, substituted cycloalkylalkyl, heterocyclyl, substitutedheterocyclyl, heterocyclylalkyl, substituted hetereocyclylalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl,substituted heteroaralkyl, aralkyl or substituted aralkyl.

“Sulfonylamino” means the group —S(O)₂NR^(hh)— where R^(hh) is hydrogenor alkyl.

“Substituted sulfonylamino” means the group —S(O)₂NR^(ii)—R^(jj), whereR^(ii) is hydrogen or optionally substituted alkyl, and R^(jj) is alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl,aralkyl or substituted aralkyl.

“Amino” or “amine” means the group —NH₂. A “divalent amine” denotes thegroup —NH—. A “substituted divalent amine” denotes the group —NR^(kk)—wherein R^(kk) is alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, acyl, substituted acyl, sulfonyl orsubstituted sulfonyl.

“Substituted amino” or “substituted amine” means the group—NR^(mm)R^(nn), wherein R^(mm) and R^(nn) are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, acyl, substituted acyl, sulfonyl, substitutedsulfonyl, or cycloalkyl provided, however, that at least one of R^(mm)and R^(nn) is not hydrogen. R^(mm)R^(nn) in combination with thenitrogen may form an optionally substituted heterocyclic or heteroarylring.

“Alkylsulfinyl” means the group —S(O)R^(oo), wherein R^(oo) isoptionally substituted alkyl.

“Alkylsulfonyl” means the group —S(O)₂R^(pp), wherein R^(pp) isoptionally substituted alkyl.

“Alkylsulfonylamino” means the group —NR^(qq)S(O)₂R^(rr), wherein R^(rr)is optionally substituted alkyl, and R^(qq) is hydrogen or alkyl.

A “primary amino substituent” means the group —NH₂.

A “secondary amino substituent” means the group —NHR^(ss), whereinR^(ss) is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, acyl, substituted acyl, sulfonyl, substitutedsulfonyl, or cycloalkyl.

A “tertiary amino substituent” means the group —NR^(ss)R^(tt), whereinR^(ss) and R^(tt) are independently alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, acyl, substitutedacyl, sulfonyl, substituted sulfonyl, or cycloalkyl.

“Quaternary ammonium substituent” means the group —N⁺R^(ss)R^(tt)R^(uu),wherein R^(ss), R^(tt) and R^(uu) are independently alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl,substituted acyl, sulfonyl, substituted sulfonyl, or cycloalkyl.

“Heteroaryl” means a monocyclic aromatic ring structure containing 5 or6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms,containing one or more, preferably 1-4, more preferably 1-3, even morepreferably 1-2, heteroatoms independently selected from the groupconsisting of O, S, and N. Heteroaryl is also intended to includeoxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiaryring nitrogen. A carbon or nitrogen atom is the point of attachment ofthe heteroaryl ring structure such that a stable aromatic ring isretained. Examples of heteroaryl groups are pyridinyl, pyridazinyl,pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl,purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl,thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl, and thelike. “Heteroarylene” means a divalent heteroaryl.

“Heterocycle” or “heterocyclyl” means a saturated or unsaturated,non-aromatic carbocyclic group having a single ring or multiplecondensed rings, e.g. a cycloalkyl group having from 5 to 10 atoms inwhich from 1 to 3 carbon atoms in a ring are replaced by heteroatoms,such as O, S, N, and are optionally fused with benzo or heteroaryl of5-6 ring members and/or are optionally substituted. Heterocyclyl isintended to include oxidized S or N, such as sulfinyl, sulfonyl andN-oxide of a tertiary ring nitrogen. Examples of heterocycle orheterocyclyl groups are morpholino, tetrahydrofuranyl, dihydropyridinyl,piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl,dihydroindolyl, and the like.

“Heterocyclylalkyl” means the group —R-Het where Het is a heterocyclegroup and R is an alkylene group.

A “substituted heteroaryl,” “substituted heterocyclyl,” or “substitutedheterocyclylalkyl” means a heteroaryl, heterocyclyl, orheterocyclylalkyl, respectively, independently substituted with 1 ormore, e.g., 1, 2, or 3, groups or substituents such as halogen, hydroxy,optionally substituted alkoxy, optionally substituted alkylthio,alkylsulfinyl, alkylsulfonyl, acyloxy, optionally substituted aryl,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted amino, optionally substituted amido, amidino,urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclylgroups, amino sulfonyl optionally N-mono- or N,N-di-substituted withalkyl, aryl or hetero aryl groups, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino,arylcarbonylamino, heteroarylcarbonylamino, carboxyl, heterocycle,substituted heterocycle, heteroaryl, substituted heteroaryl, nitro,cyano, thiol, sulfonylamino, optionally substituted alkyl, optionallysubstituted alkenyl, or optionally substituted alkynyl, attached at anyavailable point to produce a stable compound.

“Amido” means the group —C(O)NH₂. “Substituted amido” means the group—C(O)NR^(k)R^(l), wherein R^(k) and R^(l) are independently hydrogen,lower alkyl, substituted lower alkyl, aryl, substituted aryl,heteroaryl, or substituted heteroaryl, provided, however, that at leastone of R^(k) and R^(l) is not hydrogen. R^(k)R^(l) in combination withthe nitrogen may form an optionally substituted heterocyclic orheteroaryl ring.

“Amidino” means the group —C(═NR^(m))NR^(n)R^(o), wherein R^(m), R^(n),and R^(o) are independently hydrogen or optionally substituted loweralkyl.

“Acyloxy” means the group —OC(O)R^(h), where R^(h) is hydrogen, alkyl,substituted alkyl, cyclo alkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl and the like.

“Aryloxy” means the group —OAr, where Ar is an aryl, or substitutedaryl, group. “Heteroaryloxy” means groups —OHet, wherein Het is anoptionally substituted heteroaryl group.

“Arylsulfonylamino” means the group —NR^(q)S(O)₂R^(s), wherein R^(s) isoptionally substituted aryl, and R^(q) is hydrogen or lower alkyl.“Heteroarylsulfonylamino” means the group —NR^(q)S(O)₂R^(t), whereinR^(t) is optionally substituted heteroaryl, and R^(q) is hydrogen orlower alkyl.

“Alkylcarbonylamino” means the group —NR^(q)C(O)RP, wherein R^(p) isoptionally substituted alkyl, and R^(q) is hydrogen or lower alkyl.

“Arylcarbonylamino” means the group —NR^(q)C(O)R^(s), wherein R^(s) isoptionally substituted aryl, and R^(q) is hydrogen or lower alkyl.

“Heteroarylcarbonylamino” means the group —NR^(q)C(O)R^(t), whereinR^(t) is optionally substituted aryl, and R^(q) is hydrogen or loweralkyl.

“Treatment” or “treating,” when referring to protection of an animalfrom a disease, means preventing, suppressing, repressing, or completelyeliminating the disease. Preventing the disease involves administering acomposition of the present invention to an animal prior to onset of thedisease. Suppressing the disease involves administering a composition ofthe present invention to an animal after induction of the disease butbefore its clinical appearance. Repressing the disease involvesadministering a composition of the present invention to an animal afterclinical appearance of the disease.

2. METHOD OF TREATING PRADER-WILLI SYNDROME WITH A K_(ATP) CHANNELOPENER

Provided herein are methods of treating PWS by administering a K_(ATP)channel opener to a patient. The K_(ATP) channel opener may be used totreat obesity, prediabetes, diabetes, hypertension, depression, elevatedcholesterol, other obesity associated co-morbidities, ischemic andreperfusion injury, epilepsy, cognitive impairment, schizophrenia,mania, other psychotic diseases, and the like. The K_(ATP) channelopener may (a) inhibit fasting insulin secretion, (b) inhibit stimulatedinsulin secretion, (c) elevate energy expenditure, (d) elevate betaoxidation of fat, or (e) inhibit hyperphagia.

a. Combined Treatment with Reduced Dosage of Growth Hormone

The K_(ATP) channel opener may be coadministered with a human growthhormone (GH) to treat PWS. The combination therapy may be used toimprove body composition abnormalities and improve linear growth of aninfant or child with PWS, or to improve body composition abnormalitiesin an adult with PWS. The combination therapy may also be used toimprove lean body mass, decrease body fat, modulate bone mineraldensity, or normalize adult height. The therapy may also be used toimprove cognition, tone, endurance, stamina, strength, agility, or motordevelopment, or to positively affect nitrogen balance or increase energyexpenditure.

The GH dose may be 0.18-0.3 mg/kg/week, and may be administered as adaily subcutaneous injection. The baseline GH dose may also be at least0.01, 0.05, 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, or 2.0 mg/kg/week.The baseline GH dose may also be less than 0.01, 0.05, 0.1, 0.15, 0.2,0.3, 0.4, 0.5, 1.0, 1.5, or 2.0 mg/kg/week. The GH dose may be adjustedbased on the weight of the patient. The dose may also be adjusted basedon the patient's lean mass or on insulin growth factor (IGF-1) levels,such that the IGF-1 levels do not exceed 3 standard deviations above theupper limit of normal. The upper limit of normal for IGF-1 levels may be25-1000 ng/mL, and may be in a range as described in Table 1.

TABLE 1 IGF-1 Reference Levels Age Male (ng/mL) Female (ng/mL) Adult19-30 y 126-382  138-410  31-40 y 106-255  126-291  41-50 y 86-22088-249 51-60 y 87-225 92-190 61-70 y 75-228 87-178 71-80 y 31-187 25-17181-88 y 68-157 31-162 Children 1-7 d ≦31 ≦31 8-14 d ≦43 ≦43 15 d-1 y25-265 25-265 1-2 y 45-222 99-254 3-4 y 36-202 36-202 5-6 y 32-25957-260 7-8 y 65-278 97-352 9-10 y 52-330 49-461 11-12 y 80-723 101-580 13-14 y 142-855  199-658  15-16 y 176-845  236-808  17-18 y 152-668 165-526 

When administered together with the K_(ATP) channel opener, the dose ofGH may be reduced as compared to the baseline dose of GH. The reductionmay be by at least 10, 20, 50, 80, or 90% of the baseline or adjusted GHdose. The GH dosage may also be reduced by decreasing the frequency ofGH administration, such that GH is administered 6, 5, 4, 3, 2, or 1time(s) per week. The reduction in GH dose may decrease the side effectsor risks of GH, such as the induction of insulin resistance or diabetesmellitus, acromegaly, scoliosis, intracranial hypertension, neoplasm ordeath. PWS may also be treated by administering the KATP channel openerin the absence of GH.

The KATP channel opener may also be used to treat an adult patient withPWS. The adult may be greater than or equal to 18 years of age. TheK_(ATP) channel opener may normalize IGF-1 levels in the adult.Accordingly the adult may be treated with the K_(ATP) channel openerwithout having to use GH, or by using a lower dose of GH than thebaseline dose.

(1) Treatment Based on IGF-1 Levels

IGF-1 levels may be indicative of the levels of GH. Administering theKATP channel opener may allow a lower dose of GH to be administered incombination with the KATP channel opener. This may be due to an increaseIGF-1 levels mediated by the channel opener in patients with PWS.Accordingly, the dosage of the KATP channel opener may be based on IGF-1levels, such that the IGF-1 levels do not exceed 3 standard deviationsabove the upper limit of normal. The upper limit of normal for IGF-1levels may be 25-1000 ng/mL, and may be in a range as described in Table1.

b. Combined Treatment with Reduced Dosage of Psychiatric or MoodStabilizing Drugs

The K_(ATP) channel opener may be coadministered with a psychiatric ormood stabilizing drug, such as a psychotropic medication, to treat PWSby treating a PWS behavioral symptom. The PWS behavioral symptom may beobsessions, compulsions, addiction, autism or autistic tendencies,anxiety, depression, mood swings, skin picking or psychotic behavior.The psychotropic medication may be a selective serotonin reuptakeinhibitor (SSRI), norepinephrine reuptake inhibitor (NRI), noradrenergicand specific serotonergic antidepressant (NaSSA),serotonin-norepinephrine reuptake inhibitor (SNRI), serotonin antagonistand reuptake inhibitor (SARI), norepinephrine-dopamine reuptakeinhibitor, selective serotonin reuptake enhancer,norepinephrine-dopamine disinhibitor, tricyclic antidepressant,tetracyclic antidepressant, monoamine oxidase inhibitor (MAOI),N-acetylcysteine, cysteamine, oxytocin, mood stabilizer, anticonvulsant,metabotropic glutamate receptor modulator, typical antipsychotic, oratypical antipsychotic. The SSRI may be citalopram, dapoxetine,escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. TheNRI may be atomoxetine, bupropion, reboxetine, edivoxetine, tapentadolor viloxazine. The NaSSA may be mianserin or mirtazapine. The SNRI maybe desvenlafaxine, duloxetine, milnacipran, or venlafaxine. The SARI maybe etoperidone, nefazodone, or trazdone. The norepinephrine-dopaminereuptake inhibitor may be bupropion. The selective serotonin reuptakeenhancer may be tianeptine or amineptine. The norepinephrine-dopaminedisinhibitor may be agomelatine. The tricyclic antidepressant may beamitriptyline, amitriptylinoxide, clomipramine, butriptyline,clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine,dosulepin, doxepin, imipramine, imipraminoxide, lofepramine,imipraminozide, lofepramine, melitracen, metapramine, nitroxazepine,nortriptyline, noxiptiline, pipofezine, propizepine, protriptyline,quinupramine, amineptine, iprindole, opipramol, tianeptine, ortrimipramine. The tetracyclic antidepressant may be amoxapine,maprotiline, mazindol, mianserin, mirtazapine, or setiptiline. The MAOImay be isocarboxazid, phenelzine, selgiline, tranylcypromine,moclobemide, or pirlindole. The mood stabilizer may be lithium or ananticonvulsant such as valproic acid, divalproex sodium, sodiumvalproate, lamotrigine, oxcarbazepine, topiramate, riluzole, gabapentin,pregabalin, carbamazepine, vigabatrin, progabide, tiagabine, zonisamide,or phenyloin. The metabotropic glutamate receptor modulator may befenobam, mavoglurant, GRN-529, STX107, STX110, RO4917523, dipraglurant,ADX-71149/JNJ-40411813, RO4491533, or RO4995819. The typicalantipsychotic may be haloperidol, droperidol, chlorpromazine,fluphenazine, perphenazine, prochlorperazine, thioridazine,trifluorperazine, mesoridazine, periciazine, promazine, triflupromazine,levomepromazine, promethazine, pimozide, cyamemazine, chlorprothixene,clopenthixol, flupenthixol, thiothixene, or zuclopenthixol. The atypicalantipsychotic may be amisulpride, aripiprazole, asenapine, blonanserin,carpipramine, clocapramine, clotiapine, clozapine, iloperidone,lurasidone, mosapramine, olanzapine, paliperidone, perospirone,quetiapine, remoxipride, risperidone, sertindole, sulpiride,ziprasidone, zotepine, bitopertin (RG1678), cariprazine (RGH-188),LY2140023, pimavanserin (ACP-103), vabicaserin (SCA-136), or zicronapine(Lu 31-130). The baseline psychiatric drug dose may be at least 1, 5,10, 15, 20, 30, 40, 50, 100, 200, 300, 400, 500, 1000, or 2000 mg. Thedose may also be less than 1, 5, 10, 15, 20, 30, 40, 50, 100, 200, 300,400, 500, 1000, or 2000 mg. The psychiatric drug may be administeredonce, twice, three times, four times, five times, seven times, eighttimes, nine times, ten times, eleven times, or twelve times daily. Thepsychiatric drug may also be administered once every 1, 2, 3, 4, or 5weeks.

When administered together with the KATP channel opener, the dose of thepsychiatric medication may be by at least 10, 20, 50, 80, or 90% of thebaseline psychiatric medication dose. The frequency of administering thepsychiatric medication dosage may also be decreased if the psychiatricmedication is coadministered with the KATP channel opener. The decreasemay be by once, twice, three times, four times, five times, seven times,eight times, nine times, ten times, eleven times, or twelve times daily;or once twice, three times, four times, or five times per month. PWS mayalso be treated by administering the K_(ATP) channel opener in theabsence of the psychiatric medication.

c. Combined Treatment with Reduced Dosage of Wakefulness PromotingAgents

The K_(ATP) channel opener may be coadministered with a wakefulnesspromoting agent to treat PWS. The PWS symptom being treated may beexcessive daytime sleepiness, sleep apnea, narcolepsy (with or withoutcataplexy), cataplexy, hypnagogic hallucinations, hypnopompichallucinations, or sleep paralysis. The wakefulness promoting agent maybe a stimulant such as an amphetamine, a norepinephrine reuptakeinhibitor (NRI), norepinephrine-dopamine reuptake inhibitor (NDRI), atricyclic antidepressant, a serotonin-norepinephrine reuptake inhibitor(SNRI), an H3-receptor antagonist, an orexin agonist, sodium oxybate,caffeine, or a eugeroic (e.g., modanafil, adrafinil, armodafinil). Theamphetamine may be dextroamphetamine, methamphetamine, mixed amphetaminesalts (ADDERALL®), or lisdexamfetamine. The NRI may be atomoxetine,bupropion, reboxetine, edivoxetine, tapentadol or viloxazine. The NDRImay be dexmethylphenidate, fencamine, fencamfamine, or methylphenidate.The tricyclic antidepressant may be amitriptyline, amitriptylinoxide,clomipramine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dosulepin, doxepin, imipramine, imipraminoxide,lofepramine, imipraminozide, lofepramine, melitracen, metapramine,nitroxazepine, nortriptyline, noxiptiline, pipofezine, propizepine,protriptyline, quinupramine, amineptine, iprindole, opipramol,tianeptine, or trimipramine. The SNRI may be desvenlafaxine, duloxetine,milnacipran, or venlafaxine. The baseline wakefulness promoting agentdose may be at least 1, 5, 10, 15, 20, 30, 40, 50, 100, 200, 300, 400,500, 1000, or 2000 mg. The dose may also be less than 1, 5, 10, 15, 20,30, 40, 50, 100, 200, 300, 400, 500, 1000, or 2000 mg. The wakefulnesspromoting agent may be administered once, twice, three times, fourtimes, five times, seven times, eight times, nine times, ten times,eleven times, or twelve times daily. The wakefulness promoting agent mayalso be administered once every 1, 2, 3, 4, or 5 weeks.

When administered together with the KATP channel opener, the dose of thewakefulness promoting agent may be reduced as compared to the baselinedose of the wakefulness promoting agent. The reduction may be by atleast 10, 20, 50, 80, or 90% of the wakefulness promoting agent dose.The frequency of administering the wakefulness promoting agent dosagemay also be decreased if the wakefulness promoting agent iscoadministered with the K_(ATP) channel opener. The decrease may be byonce, twice, three times, four times, five times, seven times, eighttimes, nine times, ten times, eleven times, or twelve times daily; oronce twice, three times, four times, or five times per month. PWS mayalso be treated by administering the K_(ATP) channel opener in theabsence of the wakefulness promoting agent.

d. Treatment Based on Nutritional Phase

The K_(ATP) channel opener may be administered based on the PWSnutritional phase of the patient. The nutritional phase may be asdescribed in Table 2.

TABLE 2 PWS Nutritional Phase Phase Clinical Characteristics Phase 0:Decreased fetal movements Full-term birth weight and BMI are about15-20% less than the and lower birth weight siblings Typically normalgestational age 85% have decreased fetal movements Phase 1a: Hypotoniawith difficult Weak, uncoordinated suck. Usually cannot breastfeedfeeding (0-9 months) Needs assistance with feeding either throughfeeding tubes (nasal/oral gastric tube or gastrostomy tube) or orallywith special, widened nipples. Many would die without assisted feedingOral feeds are very slow Severely decreased appetite. Shows little or noevidence of being hungry Does not cry for food or get excited at feedingtime If feeding just occurred when baby “acted hungry” then would havesevere “failure-to-thrive” Weak cry Phase 1b: No difficulty feeding andNo longer needs assisted feeding growing appropriately on growth curveGrowing steadily along growth curve with normal feeding (9-25 months)Normal appetite Phase 2a: Weight increasing without Infant startscrossing growth curve centile lines an increase in appetite or excessiveNo increase in appetite calories (2.1-4.5 years) Appetite appropriatefor age Will become obese if given the recommended daily allowance (RDA)for calories or if eating a “typical” toddler diet of 70% carbohydratesTypically needs to be restricted to 60-80% of RDA to prevent obesityPhase 2b: Weight increasing with an Increased interest in food.Frequently asking “food related” increase in appetite (4.5-8 years)questions Preoccupied with food. Very concerned about the nextmeal/snack (e.g., “Did you remember to pack my lunch?”) Increasedappetite Will eat more food than a typical child if allowed Will eatfood within their line of sight if unattended Will become obese ifallowed to eat what they want Can be fairly easily redirected about foodCan feel full Will stop eating voluntarily Phase 3: Hyperphagic, rarelyfeels full Constantly thinking about food (8 years to adulthood) Whileeating one meal they are already thinking about the next meal Willawaken from sleep early thinking about food Will continue eating ifportion size is not limited Rarely (truly) feels full Will steal food ormoney to pay for food Can eat food from garbage and otherunsavory/inedible sources (e.g., dog food, frozen food, crayons, etc.)Typically are not truthful about what they have eaten (i.e. amount andtypes of food) Will gain considerable amount of weight over a shortperiod of time if not supervised (e.g., some individuals are known tohave gained up to 20 pounds in one weekend) Food typically needs to belocked up. Frequently the child will ask the parent to lock the food ifthe parent has forgotten Will break into neighbors' houses for foodTemper tantrums and “meltdowns” frequently related to food Needs to beplaced on a diet that is approximately 50-70% of the RDA to maintain ahealthy weight Phase 4: Appetite is no longer Appetite may still beincreased or may be normal or less than normal insatiable (adulthood)Previously in phase 3, but now a noticeable improvement in theirappetite control Can feel full Appetite can fluctuate in this phase, butthe key component is noticeable improvement in control of appetitecompared to when they were younger Not as preoccupied with food Absenceof major temper tantrums and “meltdowns” related to food Onset inadulthood. Could be as early as 20s or as late as 40-50s

The dose of the K_(ATP) channel opener may also be adjusted according tothe PWS nutritional phase of the patient.

The K_(ATP) channel opener may also be administered to prevent theprogression of a patient's PWS nutritional phase to a later phase. TheK_(ATP) channel opener may be administered to a PWS patient in PWSnutritional phase 1a or 1b, and may prevent the patient's PWSnutritional phase from progressing to phase 2a or 2b. In addition, theK_(ATP) channel opener may be administered to a PWS patient in PWSnutritional phase 2a or 2b, and may prevent the PWS patient'snutritional phase from progressing to phase 3 or 4.

The K_(ATP) channel opener may also be administered to shift a PWSpatient's PWS nutritional phase back to an earlier phase. The K_(ATP)channel opener may be administered to a PWS patient in PWS nutritionalphase 3 or 4, and may shift the patient's PWS nutritional phase back tophase 1a, 1b, 2a, or 2b. The K_(ATP) channel opener may also beadministered to a PWS patient in PWS nutritional phase 2a or 2b, and mayshift the patient's PWS nutritional phase back to phase 1a or 1b.

The K_(ATP) channel opener dose administered to shift a patient's PWSnutritional phase or prevent a patient's PWS nutritional phase fromadvancing may be higher for a later PWS nutritional phase than the doseadministered for an earlier PWS nutritional phase. The dose for thelater PWS nutritional phase may be 10, 20, 40, 50, 60 or 80% higher, ormay be 2, 3, 4, 5, 6, 7, 8, 9, or 10 times higher.

e. Treating Autism Symptoms Associated with PWS

The KATP channel opener may be used to treat an autism-related symptomor an autism spectrum disorder (ASD) associated with PWS. The patientmay have an elevated score on the Pervasive DevelopmentalDisorder-Mental Retardation questionnaire that is indicative of an ASD.The patient may meet the criteria for an ASD on the Autism DiagnosticObservation Schedule or the Autism Diagnostic Interview, Revised. Thepatient may have a symptom such as an impairment in social interaction,language or communication; restricted, repetitive, or stereotypedbehavior; stereotypies; a pronounced repetitive or compulsive behavior;skin picking; a need to tell, ask, or say; hoarding; ordering,arranging; symmetry or exactness; ritualized eating; rereading andrewriting; fearful of losing things; repeated checking; touching,tapping and rubbing; excessive washing; rectal picking; repetition ofroutines; or pulling hair out.

3. METHOD OF TREATING PRADER-WILLI SYNDROME AND CONDITIONS ASSOCIATEDWITH LOW BASAL METABOLIC RATE OR HYPERPHAGIA BASED ON BLOOD KETONELEVELS

Provided herein is a method of treating PWS or conditions associatedwith low basal metabolic rate or hyperphagia by administering theK_(ATP) channel to a patient. The condition may be obesity. The K_(ATP)channel opener may be administered according to a PWS patient's bloodketone level. The patient's blood ketone level may be less than or equalto a target level of 3.0, 2.5, 2.0, 1.5, 1.0, 0.6, 0.5, 0.4, 0.3, 0.2,or 0.1 mmol/L. The patient's target level may also be 0.6-1.5 mmol/L,1.6-3.0 mmol/L, less than or equal to 1.4, 1.5 or 1.6 mmol/L, or greaterthan or equal to 1.5 mmol/L or 3.0 mmol/L. The dose of the K_(ATP)channel opener may be increased for the patient in comparison to thepatient's previous dose until the patient's blood ketone level is atleast at the target level. The dose of the K_(ATP) channel opener beingadministered to the patient may be maintained if the patient's bloodketone level is at the target level. The dose of the K_(ATP)administered to the patient may be decreased in comparison to thepatient's previous dose until the patient's blood ketone level is lessthan or equal to the target level. The dose of the K_(ATP) channelopener may also be decreased in the event that the patient experiencesan undesirable side effect, such as hyperglycemia.

4. K_(ATP) CHANNEL OPENER

The K_(ATP) channel opener may have the structure of one of FormulaI-VIII.

In Formula I,

R1 may be hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, orsubstituted cycloalkyl, provided however that when R1 is a substitutedlower alkyl or a substituted cycloalkyl, then the substituent may notinclude an amino group;

R2a may be hydrogen;

X may be a 1, 2 or 3 atom chain, in which each atom is independentlyhalogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy,cycloalkyl, substituted cycloalkyl, or substituted lower alkoxy,provided however that when an atom of the chain is substituted withsubstituted lower alkyl, substituted lower alkoxy or substitutedcycloalkyl, then the substituent may not include an amino group; and

ring B may be saturated, monounsaturated, polyunsaturated or aromatic.

In Formula I, X may also be C(Ra)C(Rb), and Ra and Rb may beindependently hydrogen, halogen, lower alkyl, substituted lower alkyl,cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted loweralkoxy, sulfonyl, or the like. Ra and Rb may also be independentlyselected from hydroxyl, substituted oxy, substituted thiol, alkylthio,substituted alkylthio, sulfinyl, sulfonyl, substituted sulfinyl,substituted sulfonylalkylsulfinyl, alkylsulfonyl, and the like. Ring Bmay not include any heteroatoms.

Salts of the channel openers defined by Formula I may be prepared fromthe following: (a) metal hydroxides, preferably alkali metal hydroxides(e.g., NaOH and KOH) and (b) organic hydroxides, preferably organiccompounds which include at least one tertiary amine or at least onequaternary ammonium ion (e.g., diethylamine ethanol, triethylamine,hydroxyethylpyrrolidine, choline and hexamethylhexamethylenediammonium,and the like).

In Formula II,

R1 may be hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, orsubstituted cycloalkyl, provided however that when R1 is a substitutedlower alkyl or a substituted cycloalkyl, then the substituent may notinclude an amino group;

R2b may be hydrogen;

X may be a 1, 2 or 3 atom chain, in which each atom is independentlycarbon, sulfur or nitrogen, and each atom may be optionally substitutedwith halogen, hydroxyl, lower alkyl, substituted lower alkyl, loweralkoxy, cycloalkyl, substituted cycloalkyl, or substituted lower alkoxy,provided however that when an atom of the chain is substituted withsubstituted lower alkyl, substituted cycloalkyl or substituted loweralkoxy, then the substituent may not include an amino group; and

ring B may be saturated, monounsaturated, polyunsaturated or aromatic.

In Formula II, X may also be C(Ra)C(Rb), in which Ra and Rb areindependently hydrogen, halogen, lower alkyl, substituted lower alkyl,cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted loweralkoxy, sulfonyl, or the like. Ra and Rb may also be independentlyhydroxyl, substituted oxy, substituted thiol, alkylthio, substitutedalkylthio, sulfinyl, sulfonyl, substituted sulfinyl, substitutedsulfonyl, alkylsulfinyl, alkylsulfonyl, nitro or the like. Ring B maynot include any heteroatoms.

Salts of the channel openers defined by Formula II may be prepared fromthe following: (a) metal hydroxides, preferably alkali metal hydroxides(e.g., NaOH and KOH) and (b) organic hydroxides, preferably organiccompounds which include at least one tertiary amine or at least onequaternary ammonium ion (e.g., diethylamine ethanol, triethylamine,hydroxyethylpyrrolidine, choline and hexamethylhexamethylenediammonium,and the like).

In Formula III,

R1 may be hydrogen, lower alkyl, substituted lower alkyl, or cycloalkyl,provided however that when R1 is a substituted lower alkyl, then thesubstituent may not include an amino group;

R2a may be hydrogen;

R3 may be hydrogen, halogen, lower alkyl, substituted lower alkyl,cycloalkyl or substituted cycloalkyl, provided however that when R3 is asubstituted lower alkyl, then the substituent may not include an aminogroup; and

R4 may be hydrogen, halogen, lower alkyl, substituted lower alkyl,cycloalkyl or substituted cycloalkyl, provided however that when R4 is asubstituted lower alkyl, then the substituent may not include an aminogroup

In Formula III, R1 may also be a lower alkyl, (ethyl or methyl); R2a maybe hydrogen; and R3 and R4 may each independently be halogen.

In Formula III, R1 may also be methyl; R2a may be hydrogen; R3 may behydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, orsubstituted cycloalkyl; and R4 may be chlorine.

Salts of the channel openers defined by Formula III may be prepared fromthe following: (a) metal hydroxides, preferably alkali metal hydroxides(e.g., NaOH and KOH) and (b) organic hydroxides, preferably organiccompounds which include at least one tertiary amine or at least onequaternary ammonium ion (e.g., diethylamine ethanol, triethylamine,hydroxyethylpyrrolidine, choline and hexamethylhexamethylenediammonium,and the like).

In Formula IV,

R1 may be hydrogen, lower alkyl, substituted lower alkyl, or cycloalkyl,provided however that when R1 is a substituted lower alkyl, then thesubstituent may not include an amino group;

R2b may be hydrogen;

R3 may be hydrogen, halogen, lower alkyl, substituted lower alkyl,cycloalkyl or substituted cycloalkyl, provided however that when R3 is asubstituted lower alkyl, then the substituent may not include an aminogroup; and

R4 may be hydrogen, halogen, lower alkyl, substituted lower alkyl,cycloalkyl or substituted cycloalkyl, provided however that when R4 is asubstituted lower alkyl, then the substituent may not include an aminogroup.

In Formula IV, R1 may also be a lower alkyl, (ethyl or methyl); R2b maybe hydrogen; and R3 and R4 may each independently be halogen.

In Formula IV, R1 may also be methyl; R2b may be hydrogen; R3 may behydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, orsubstituted cycloalkyl; and R4 may be chlorine.

Salts of the channel openers defined by Formula IV may be prepared fromthe following: (a) metal hydroxides, preferably alkali metal hydroxides(e.g., NaOH and KOH) and (b) organic hydroxides, preferably organiccompounds which include at least one tertiary amine or at least onequaternary ammonium ion (e.g., diethylamine ethanol, triethylamine,hydroxyethylpyrrolidine, choline and hexamethylhexamethylenediammonium,and the like).

In Formula V,

R1 may be optionally substituted amino, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, or optionally substitutedheteroarylalkyl;

R2a may be hydrogen, and lower alkyl;

X may be a 1, 2 or 3 atom chain, in which each atom is independentlycarbon, sulfur or nitrogen, and each atom may be optionally substitutedwith halogen, hydroxyl, optionally substituted lower alkyl, optionallysubstituted lower alkoxy, optionally substituted cycloalkyl, oroptionally substituted amino;

ring B may be saturated, monounsaturated, polyunsaturated or aromatic;and at least one of R1 or a substituent of X may include an amino group.

In Formula V, X may be C(Ra)C(Rb), in which Ra and Rb may beindependently hydrogen, halogen, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substituted lower alkoxy,amino, sulfonylamino, aminosulfonyl, sulfonyl, or the like. R1 may alsoinclude at least one substituent containing an amino group. Ra and Rbmay be independently hydroxyl, substituted oxy, substituted thiol,alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substitutedsulfinyl, substituted sulfonyl, substituted sulfonylamino, substitutedamino, substituted amine, alkylsulfinyl, alkylsulfonyl,alkylsulfonylamino, or the like. Ring B may not include any heteroatoms.

In Formula VI,

R1 may be optionally substituted amino, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, or optionally substitutedheteroarylalkyl;

R2b may be hydrogen or lower alkyl;

X may be a 1, 2 or 3 atom chain, in which each atom is independentlycarbon, sulfur or nitrogen, and each atom may be optionally substitutedwith halogen, hydroxyl, optionally substituted lower alkyl, optionallysubstituted lower alkoxy, optionally substituted cycloalkyl, oroptionally substituted amino;

ring B may be saturated, monounsaturated, polyunsaturated or aromatic;and

at least one of R1 or a substituent of X may include an amino group.

In Formula VI, X may also be C(Ra)C(Rb), in which Ra and Rb may beindependently hydrogen, halogen, lower alkyl, substituted lower alkyl,cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted loweralkoxy, amino, sulfonylamino, amino sulfonyl, sulfonyl, or the like. Raand Rb may be independently hydroxyl, substituted oxy, substitutedthiol, alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substitutedsulfinyl, substituted sulfonyl, substituted sulfonylamino, substitutedamino, substituted amine, alkylsulfinyl, alkylsulfonyl,alkylsulfonylamino, or the like. R1 may include at least one substituentcontaining an amino group. Ring B may not include any heteroatoms.

In Formula VII,

R1 may be optionally substituted amino, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, or optionally substitutedheteroarylalkyl;

R2a may be hydrogen, lower alkyl, or substituted lower alkyl;

R3 may be hydrogen, halogen, optionally substituted lower alkyl,optionally substituted amino, optionally substituted cycloalkyl oroptionally substituted aryl;

R4 may be hydrogen, halogen, optionally substituted lower alkyl,optionally substituted amino, optionally substituted cycloalkyl oroptionally substituted aryl; and

at least one of R1, R3 and R4 may include a substituent containing anamino group.

Preferably, R1 includes a substituent containing an amino group. Inparticular embodiments of Formula VII; R1 includes an amino substituent,R2a is hydrogen; and R3 and R4 are each independently halogen.

In Formula VII, R2a may be hydrogen; R3 may be hydrogen, halogen, loweralkyl, substituted lower alkyl, amino, substituted amino, cycloalkyl, orsubstituted cycloalkyl; and R4 may be chlorine.

In Formula VIII,

R1 may be optionally substituted amino, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, or optionally substitutedheteroarylalkyl;

R2b may be hydrogen, lower alkyl, or substituted lower alkyl;

R3 may be hydrogen, halogen, optionally substituted lower alkyl,optionally substituted amino, optionally substituted cycloalkyl oroptionally substituted aryl;

R4 may be hydrogen, halogen, optionally substituted lower alkyl,optionally substituted amino, optionally substituted cycloalkyl oroptionally substituted aryl; and

at least one of R1, R3 and R4 may include a substituent containing anamino group.

R1 may include a substituent containing an amino group. R2b may behydrogen; and R3 and R4 may each independently be halogen.

In Formula VIII, R2b may also be hydrogen; R3 may be hydrogen, halogen,lower alkyl, optionally substituted lower alkyl, optionally substitutedamino, or optionally substituted cycloalkyl; and R4 may be chlorine.

The KATP channel opener may also have the formula7-chloro-3-methyl-2-H-1,2,4-benzothiadiazine 1,1 dioxide (shown belowwith its tautomer) with the empirical formula C8H7ClN2O2S and amolecular weight of 230.7.

The KATP channel opener may also be a salt of one of the compoundsdescribed by Formulae I-VIII and may have at least one, of the followingproperties: (1) opening SURx/Kir6.y potassium channels, in which x=1, 2Aor 2B and y=1 or 2; (2) binding to the SURx subunit of KATP channels;and (3) inhibiting glucose induced release of insulin followingadministration of the compound in vivo.

The KATP channel opener may also be a structural variant orbioequivalent of a compound defined by Formulae I-VIII, such as aderivative, salt, prodrug or isomer thereof. The salt of KATP channelopener may have a cation that is a cation of an alkali metal or anorganic compound which includes a tertiary amine or a quaternaryammonium ion. If the salt includes an anion of diazoxide and a sodiumcation, then the salt may not be in a form suitable for intravenous use.If the anion is diazoxide in a solution suitable for intravenous use,then the cation may not be sodium. In solutions suitable for intravenoususe, if the cation is sodium, then the anion may not be an anion ofdiazoxide. If the salt includes an anion of diazoxide and a sodiumcation, then the salt may not be in liquid form. The KATP channel openermay be a salt of a compound of one of Formulae I-VIII in which thecation is sodium, potassium, choline or hexamethyl hexamethylenediammonium. The KATP channel opener may also be BPDZ 62, BPDZ 73, NN414,or BPDZ 154. For salts of compounds of Formula V-VIII, at least onesubstituent of the compound of Formulae V-VIII may include an aminogroup. The compound of Formula V-VIII may form an anion of a salt and amonovalent or divalent metal may form the cation. The cation may includea tertiary amino or quaternary ammonium group.

a. Dosage

The dose of the K_(ATP) channel opener may be at least 1, 5, 10, 15, 20,30, 40, 50, 100, 200, 300, 400, 500, 1000, or 2000 mg. The dose may alsobe less than 1, 5, 10, 15, 20, 30, 40, 50, 100, 200, 300, 400, 500,1000, or 2000 mg. The dose may further be determined based on the weightof the subject for which it is to be administered, such that theformulation may contain a single administration dose of at least 0.1,0.5, 1.0, 2.0, 3.0, 5.0, 10.0, or 20.0 mg per kg of the subject's bodyweight. The formulation may also contain a single administration dose ofless than 0.1, 0.5, 1.0, 2.0, 3.0, 5.0, 10.0, or 20.0 mg per kg of thesubject's body weight.

The efficacy of the K_(ATP) channel opener may be enhanced or reduced bythe composition of the patient's diet. Diets high in carbohydrates(e.g., >40% of calories from carbohydrates) may require higher doses ofdiazoxide to achieve optimal results. In contrast, a patient consuming ahigher protein content diet (e.g. >15% of calories from protein) orhigher fat content (e.g., >30% of calories from fat) may require lowerdoses of diazoxide to achieve optimal results. The variability inpatients' diets and the impact of dietary composition on the drug'sefficacy also lends itself to using a biomarker like blood ketone levelsto monitor or titrate the patient's dose of diazoxide.

b. Compositions

This invention also relates to a method of treatment comprisingadministering a composition comprising a K_(ATP) channel opener, whichmay be a therapeutically effective amount. The composition may be apharmaceutical composition, which may be produced using methods wellknown in the art.

c. Administration

Administration of the composition using the method described herein maybe orally, parenterally, sublingually, transdermally, rectally,transmucosally, topically, via inhalation, via buccal administration, orcombinations thereof. Parenteral administration includes, but is notlimited to, intravenous, intraarterial, intraperitoneal, subcutaneous,intramuscular, intrathecal, and intraarticular. The compositions may beadministered to a human patient, cat, dog, large animal, or an avian.The composition may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12 times per day.

d. Formulation

The compositions provided herein may be in the form of capsules,sprinkle formulation, tablets or lozenges formulated in a conventionalmanner. For example, tablets and capsules for oral administration maycontain conventional excipients including, but not limited to, bindingagents, fillers, lubricants, disintegrants and wetting agents. Bindingagents include, but are not limited to, syrup, accacia, gelatin,sorbitol, tragacanth, mucilage of starch and polyvinylpyrrolidone.Fillers include, but are not limited to, lactose, sugar,microcrystalline cellulose, maizestarch, calcium phosphate, andsorbitol. Lubricants include, but are not limited to, magnesiumstearate, stearic acid, talc, polyethylene glycol, and silica.Disintegrants include, but are not limited to, potato starch and sodiumstarch glycollate. Wetting agents include, but are not limited to,sodium lauryl sulfate. Tablets may be coated according to methods wellknown in the art.

Compositions provided herein may also be liquid formulations including,but not limited to, aqueous or oily suspensions, solutions, emulsions,syrups, and elixirs. The compositions may also be formulated as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain additives including, but notlimited to, suspending agents, emulsifying agents, nonaqueous vehiclesand preservatives. Suspending agents include, but are not limited to,sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin,hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel,and hydrogenated edible fats. Emulsifying agents include, but are notlimited to, lecithin, sorbitan monooleate, and acacia. Nonaqueousvehicles include, but are not limited to, edible oils, almond oil,fractionated coconut oil, oily esters, propylene glycol, and ethylalcohol. Preservatives include, but are not limited to, methyl or propylp-hydroxybenzoate and sorbic acid.

Compositions provided herein may also be formulated as suppositories,which may contain suppository bases including, but not limited to, cocoabutter or glycerides. Compositions provided herein may also beformulated for inhalation, which may be in a form including, but notlimited to, a solution, suspension, or emulsion that may be administeredas a dry powder or in the form of an aerosol using a propellant, such asdichlorodifluoromethane or trichlorofluoromethane. Compositions providedherein may also be formulated as transdermal formulations comprisingaqueous or nonaqueous vehicles including, but not limited to, creams,ointments, lotions, pastes, medicated plaster, patch, or membrane.

Compositions provided herein may also be formulated for parenteraladministration including, but not limited to, by injection or continuousinfusion. Formulations for injection may be in the form of suspensions,solutions, or emulsions in oily or aqueous vehicles, and may containformulation agents including, but not limited to, suspending,stabilizing, and dispersing agents. The composition may also be providedin a powder form for reconstitution with a suitable vehicle including,but not limited to, sterile, pyrogen-free water.

Compositions provided herein may also be formulated as a depotpreparation, which may be administered by implantation or byintramuscular injection. The compositions may be formulated withsuitable polymeric or hydrophobic materials (as an emulsion in anacceptable oil, for example), ion exchange resins, or as sparinglysoluble derivatives (as a sparingly soluble salt, for example).

The present invention has multiple aspects, illustrated by the followingnon-limiting examples.

Example 1 Treating PWS

This example shows how a K_(ATP) channel opener addresses abnormalitiesobserved in patients with PWS. In particular, the channel openerdiazoxide may hyperpolarize hypothalamic neurons in a manner similar toleptin.

Diazoxide has now been prescribed at low doses for an infant with PWSwho had experienced hypoglycemic episodes. The infant was in PWSnutritional phase 1a transitioning to phase 1b was started at 0.5 mg/kgBID of diazoxide at eight months of age, increasing to 1 mg/kg BID. Nochanges in blood pressure or heart rate were observed, and no signs ofedema were present. Within two weeks of starting diazoxide, the infant'sstrong narcoleptic response to solid foods had been virtuallyeliminated. Subjectively, her energy level and stamina also improved,and her therapists documented her significant progress. The infant'sbaseline IGF-1 levels were 152 ng/mL while on 0.8 mg QD of Genotropin.Around three weeks after starting diazoxide levels, the IGF-1 levels hadrisen to 185 ng/ml, and the Genotropin was reduced to 0.6 mg QD with nodecline in energy level. Two and half weeks later, despite the declinein growth hormone dosage, the patient's IGF-1 levels had continued torise to 210 ng/ml. A significant increase in smiling over this periodwas noted. This child has not progressed to PWS nutritional phase 2a fora period of 56 weeks, perhaps as a result of the administration ofdiazoxide.

With respect to safety, no side effects have been reported for a periodof 56 weeks. The infant's blood sugar levels were monitored and were inthe normal range. Minimal or no excess lanugo hair growth had beennoted. Taken together, this case supports the utility of diazoxide inthe treatment of PWS.

1. A method for treating Prader-Willi Syndrome, comprising administeringa K_(ATP) channel opener and a human growth hormone (GH) to a patient inneed thereof, wherein the dose of human growth hormone is reduced incomparison to a baseline or adjusted GH dose.
 2. The method of claim 1,wherein the baseline or adjusted GH dose is reduced by at least 10, 20,50, 80, 90, or 100%.
 3. A method for treating Prader-Willi Syndrome,comprising administering a K_(ATP) channel opener and a psychiatric ormood stabilizing drug to a patient in need thereof, wherein the dose ofthe psychiatric or mood stabilizing drug is reduced in comparison to abaseline psychiatric or stabilizing drug dose.
 4. The method of claim 3,wherein the baseline psychiatric medication dose is reduced by at least10, 20, 50, 80, 90, or 100%.
 5. The method of claim 3, wherein thepsychiatric or mood stabilizing drug is selected from the groupconsisting of a selective serotonin reuptake inhibitor (SSRI), anorepinephrine reuptake inhibitor (NRI), a noradrenergic and specificserotonergic antidepressant (NaSSA), a serotonin-norepinephrine reuptakeinhibitor (SNRI), a serotonin antagonist and reuptake inhibitor (SARI),a norepinephrine-dopamine reuptake inhibitor, a selective serotoninreuptake enhancer, a norepinephrine-dopamine disinhibitor, a tricyclicantidepressant, a tetracyclic antidepressant, a monoamine oxidaseinhibitor (MAOI), N-acetylcysteine, cysteamine, oxytocin, a moodstabilizer, an anticonvulsant, a metabotropic glutamate receptormodulator, a typical antipsychotic, and an atypical antipsychotic.
 6. Amethod for treating Prader-Willi Syndrome, comprising administering aK_(ATP) channel opener and a wakefulness promoting agent to a patient inneed thereof, wherein the dose of the wakefulness promoting agent isreduced in comparison to a baseline wakefulness promoting agent dose. 7.The method of claim 7, wherein the baseline wakefulness promoting agentdose is reduced by at least 10, 20, 50, 80, 90, or 100%.
 8. The methodof claim 7, wherein the wakefulness promoting agent is selected from thegroup consisting of a stimulant, an amphetamine, a norepinephrinereuptake inhibitor (NRI), a norepinephrine-dopamine reuptake inhibitor(NDRI), a tricyclic antidepressant, a serotonin-norepinephrine reuptakeinhibitor (SNRI), an H3-receptor antagonist, an orexin agonist, sodiumoxybate, caffeine, and a eugeroic.
 9. A method for treating Prader-WilliSyndrome comprising administering a K_(ATP) channel opener to a patientin need thereof, wherein the patient is in a PWS nutritional phaseselected from the group consisting of 0, 1a, 1b, 2a, 2b, 3, and
 4. 10.The method of claim 10, wherein the patient's PWS nutritional phase isprevented from progressing to a later phase.
 11. The method of claim 11,wherein the patient is in PWS nutritional phase 1a, 1b, 2a, or 2b andwherein the patient's PWS nutritional phase is prevented fromprogressing to phase 1b, 2a, 2b, or
 3. 12. The method of claim 10,wherein the patient's PWS nutritional phase is shifted back to anearlier PWS nutritional phase.
 13. The method of claim 13, wherein thepatient is in PWS nutritional phase 3 or 4, and wherein the patient'sPWS nutritional phase is shifted back to phase 1a, 1b, 2a, or 2b.
 14. Amethod for treating a disease or condition selected from the groupconsisting of Prader-Willi Syndrome, a condition associated with lowbasal metabolic rate, and a condition associated with hyperphagia,comprising administering a K_(ATP) channel opener to a patient in needthereof, wherein the patient's blood ketone level is less than a targetlevel selected from the group consisting of 3.0, 2.5, 2.0, 1.5, 1.0,0.6, 0.5, 0.4, 0.3, 0.2, and 0.1 mmol/mL.
 15. The method of claim 14,further comprising the step of administering a subsequent dose of theK_(ATP) channel opener to the patient, wherein the subsequent dose ishigher than the previous dose if the patient's blood ketone level isless than or equal to the target level after administration of theprevious dose, and wherein the subsequent dose is equal to or less thanthe previous dose if the patient's blood ketone level is greater than orequal to the target level after administration of the previous dose. 16.A method for treating autistic symptoms or behaviors associated withPrader-Willi Syndrome comprising administering a K_(ATP) channel openerto a patient in need thereof.